Expert Perspectives on the Treatment of Melanoma - Episode 4

Melanoma: Optimizing Selection of Adjuvant Therapy


Dirk Schadendorf, MD, PhD: I disagree. I think what we have to keep in mind that in stage III disease, with just the surgery we are curing, is in roughly one-third of the patients. I mean, in multiple trials including the EORTC [European Organisation for Research and Treatment of Cancer] trial, we have seen after 5 years roughly one-third of the patients would not have needed any adjuvant treatments.

Alexander Eggermont, MD, PhD: No, two-thirds. Well, actually it’s 54% in ipilimumab trial who are cured at the 5-year mark, and it’s 65% who are without relapse at 5 years.

Dirk Schadendorf, MD, PhD: And one has to keep in mind that…if you look at the kinetics of relapses, for patients who had in the placebo arm—this is true for the old ipilimumab trial as well as for the COMBI-AD—most of the relapses do occur within the first 18 to 20 months. And you have a stabilization of the curve, even if the placebo adds to the patient population, which stabilizes after 24, 30 months. That’s what you see with all the other curves as well. That’s the reason why I don’t believe there will be a crossing of the curves with the checkpoint inhibitors.

Because most of the relapses do occur within the first 30 months, and after that you have the stabilization of the curve. That’s what was shown with targeted therapy with a calculation of a cure rate, and that’s what you will be able to do also with the checkpoint inhibitors. I believe the curves will stay very close together and it will be hard to discriminate if you compare the different trials. I mean, we can have a discussion on different patient selection, who was included, and all that, but I think that’s academic. For the patient, it’s clear it’s very close. And with the kinetics—as Alex described, that was checkpoint inhibition—you have a certain chance to have a relapse early, because too much is controlled within the treatment period. For the targeted therapy you have the risk after stopping the treatment that some patients start to have regrowth. At the end for this 60%, 70% of patients, probably they have a good chance to be cured.

Alexander Eggermont, MD, PhD: Still, I must remind you of advanced disease. Three-year survival rates with nivolumab-ipilimumab, or 68% for BRAF-mutant patients. For BRAF-mutant patients, the 3-year survival rate for a BRAF/MEK combo is 45%. I’m sorry, that is a huge difference, and I put a bottle of Dom Pérignon on it if they cross also in the adjuvant setting. I’m totally convinced of that because immunotherapy is simply superior.

Caroline Robert, MD, PhD: Yeah, but you all these contingents of patients who will not relapse. So it’s not like metastatic disease, where they will all relapse. This is different.

Alexander Eggermont, MD, PhD: You will see the curves will cross at 2½ years. I promise you the curves will cross....I promise you.

Sanjiv S. Agarwala, MD: I think what we’ll do now is, I think from the discussion it’s obvious that there [are] some really good data out there. We have to look at it carefully.

Caroline Robert, MD, PhD: That’s why it’s not easy when you explain it to the patient.

Sanjiv S. Agarwala, MD: It’s not easy, exactly. I’m going to go back to you, Caroline. You mentioned earlier patient selection. [In] my clinic, when I talk about this, I do exactly what you do, which is discuss different options. And I kind of tell them that simplistically it’s chronic toxicity that we can quickly turn off when you stop the oral drugs for BRAF-MEK. With the immunotherapy mostly you will not have a toxicity, but if you do, it could be longer lasting. Is that what you do? Are there any patient factors specifically that drive you to advise a patient 1 way or the other?

Caroline Robert, MD, PhD: Yes, of course. If you have an...activity maybe...

Sanjiv S. Agarwala, MD: [Let’s] say [there’s] no autoimmune disease, just a patient. Any other factors?

Caroline Robert, MD, PhD: Uh, in transplant organ.

Sanjiv S. Agarwala, MD: OK, yeah.

Caroline Robert, MD, PhD: No. Or a patient who’s not going to be reliable, [who is] not going to call me if he has a problem.

Sanjiv S. Agarwala, MD: So they need the oral drugs for that.

Caroline Robert, MD, PhD: Yes.

Sanjiv S. Agarwala, MD: How do you then ensure compliance [that] they’re taking the drugs at home?

Caroline Robert, MD, PhD: We see them every month. We call them every week if we don’t hear from them—and yeah, at least every month. I also try honestly to tell every patient. And it’s difficult in this setting of adjuvant, where patients are not so sick sometimes. But I always oblige myself to tell them that there are very serious adverse events that I can’t cure with anti—PD-1, even for that. and it’s very difficult to say that, because it really frightens them a lot. But I think we have to tell them [that] it’s extremely rare, but it can happen. Because I think if you don’t tell them, I mean, they can reproach that. Why didn’t you tell me already complete myocarditis.

Sanjiv S. Agarwala, MD: It’s important to discuss with a patient every aspect.

Caroline Robert, MD, PhD: I really think we need to do that.

Transcript Edited for Clarity